A. Post-operative Ileus
Post-operative ileus is a common clinical problem for which there is no effective treatment. Following an operation, gastrointestinal motor failure ensues for several days; food and fluids are not tolerated, and no flatus or stool is passed per rectum. Studies of motor activity in animals have shown that contractions return first in the small intestine 3 to 6 hours after laparotomy, in the stomach after 24 hours and in the colon after several days (Arch Surg 1977; 112:203, Surgery 1978; 84:527). Analogues human studies confirm that the colon is slowest to recover (Gut 1975; 16:689, Ann Surg 1986; 203:574). Furthermore, motility patterns do not return entirely to normal as soon as contractions return so that normal digestive function is delayed. This reduces the rate of patient mobilization and recovery, and may also reduce or delay absorption of drugs administered by the GI tract. As a result, post operative ileus generally prolongs length of stay in the hospital.
The factors influencing the duration of ileus are varied. Manipulation of the abdominal organs delays return of function longer than laparotomy alone. Chemical or physical irritants in the peritoneal cavity such as bile, blood or talc delay recovery even longer. Bowel dilatation from gas and fluid accumulation activates visceral afferents and an inhibitory reflex arc (Scan J Gastro 1979; 14:101). Somatic inhibitory reflexes are activated at the beginning of a laparotomy when the parietal peritoneum is entered. The mediator involved in post-operative ileus are unknown. Adrenergic inhibition has been considered to be the cause; however, it does not explain why the process lasts several days. Plasma concentrations of catecholamines are elevated after general anesthesia and laparotomy, but the benefit of adrenalectomy, demalullation, or adrenergic antagonists in reducing ileus is controversial (Arch Surg 1977; 112:203).
In addition to the effects of surgery, the residual effects of anesthetic agents, and particularly by opioids administered for post-operative pain relief may also play a role in the development of post-operative ileus. Therefore, currently it is believed that although stimulation of the sympathetic nervous system following a laparotomy may play a role, mechanisms other than spinal reflexes (through the sympathetic nervous system) contribute significantly to the development and maintenance of post-operative ileus (Gastro 1975; 68:466).
Pharmacological approach in the treatment of post-operative ileus has been rather disappointing. Cisapride, a synthetic substituted piperidinyl benzamide is commercially available for treating gastric stasis syndrome. However, the efficacy of the drug has come into question. A randomized, double-blind, placebo-controlled study in patients undergoing elective upper gastrointestinal or colonic surgery showed no difference between the cisapride-treated and placebo-treated patients in shortening the duration of post-operative ileus. See B. Hallerback et al., "Cisapride in the Treatment of Post-Operative Ileus," Aliment Pharmocol. Ther. 5:503 (1991).
The drug cholecystokinin (CCK) has also been tested on patients with post-operative ileus. However, in a randomized, double-blind trial, no differences were found between the CCK-treated group and the placebo group. See J. Frisell et al., "The Effect of Cholecystokinin on Post-Operative Bowel Function," Acta Chir. Scand. 151:557 (1985).
The effects of dihydroergotamine (DHE) on post-operative ileus has also been examined in patients following major abdominal surgery. There were no significant differences between DHE-treated patients and controls in the duration of post-operative ileus. See J. Thorup et al., "DiHydro Ergotamine in Post-Operative Ileus," Clin. Pharmacol. Ther. 34:54 (1983).
What is needed is a treatment approach that is effective in shortening the duration of post-operative ileus. Such an approach should be specific with minimum involvement of organs other than the colon.
B. Constipation
Constipation is one of the most common clinical problems in the western world. In the United States, 368 million dollars were spent for laxatives in 1982 (Am J Gastro 1985; 80:303); some are used unnecessarily, and many may be harmful. No data exist regarding additional costs generated as a result of medical evaluations, diagnostic studies, surgery, and absences from work relating to constipation.
Constipation may be conceptually regarded as disordered movement through the colon because, with few exceptions, transit through the more proximal regions of the GI tract are normal. From a pathophysiologic viewpoint, impairment of large intestine transit can occur because of a primary motor disorder, in association with a large number of diseases, or as a side effect of many drugs. However, the vast majority of constipated patients have no obvious cause to explain their symptoms but are presumed to have an underlying disorder of colonic or anorectal function.
In addition to dietary ad behavioral approaches, pharmacologic therapy remains the main stay in the treatment of chronic constipation and vast amounts are consumed in the western world, especially by elderly persons. Laxatives are classified into five groups on the basis of their presumed mode of action. These include bulk forming laxatives, emollient laxatives, hyperosmolar laxatives, saline laxatives, and stimulant laxatives. Except for the bulk laxatives, routine use of these agents over long periods of time should be discouraged because of potential serious side effects on the colonic nervous and muscular systems.
Recently prokinetic agents that stimulate gastrointestinal motor activity to enhance transit of intraluminal contents have been used to treat chronic constipation. Both metoclopramide and cisapride which have been used to treat upper GI motor disorders exert little effect on colonic motility and are not very effective in constipated patients (Functional disorders of the GI tract, In: Cohen S, Soloway R D eds. New York: Churchill Livingstone, 1987:95). Ideally an agent which is derived from a naturally occurring substance in the GI tract, which stimulate colonic peristalsis would be ideal in the treatment of colonic constipation.
C. Irritable Bowel Syndrome (IBS)
IBS is the most prevalent digestive disease accounting for 12% of visits to primary care physicians and 28% of referrals to gastroenterologists (Gastroenterology 1987; 92:1282). Over 2 million prescriptions are written for IBS (Gastroenterology 1990; 99:409).
IBS is a heterogeneous disorder with distinct symptom presentations. Abdominal pain and irregular bowel habits are the major complaints. IBS patients with predominant diarrhea symptoms only account for 20% of the IBS patients. Most other IBS patients present with either constipation or constipation alternating with diarrhea. With constipation, stools usually are hard and may be scybalous or pellet-like. Long periods of straining may be required for fecal evacuation. Constipation can persist for weeks to months, interrupted by brief periods of diarrhea. Other frequent associated symptoms are abdominal cramps, gas and bloating.
Regulation of bowel function is an important aspect of the treatment of constipation, abdominal cramps, gas and bloating. Treatment with increased dietary fiber and/or osmotic laxatives may promote more rapid transit and relieve constipation and functional obstruction. However control trials indicate that fiber supplementation is no better than placebo for the IBS population as a whole (Gastroenterology 1988; 95:232), however some constipated patients may respond to intensive fiber treatment. Prokinetic agents such as cisapride has been shown to increase stool frequency and accelerate whole gut transit in IBS patients (Progr Med 1987; 43:121) and may provide some clinical benefits to constipation IBS patients (J Clin Gast 1991; 13:49, Aliment Pharmacol Ther 1997; 11:387). However, since cisapride acts primarily on the upper gut, subsequent clinical experience has been disappointing in IBS patients with severe constipation. An agent which acts specifically to initiate peristalsis in the colon should provide better clinical response.